4-3135947-G-A

Variant names:

• chr4-3135947-G-A
• rs363075
• NM_001388492.1:c.2677G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001388492.1(HTT):​c.2677G>A​(p.Gly893Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0526 in 1,603,158 control chromosomes in the GnomAD database, including 2,493 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.041 (168 hom., cov: 32)
  • Exomes 𝑓: 0.054 (2325 hom.)
• Consequence: HTT NM_001388492.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.74
• Publications: 23 publications found

Genes affected

HTT (HGNC:4851): (huntingtin) Huntingtin is a disease gene linked to Huntington's disease, a neurodegenerative disorder characterized by loss of striatal neurons. This is thought to be caused by an expanded, unstable trinucleotide repeat in the huntingtin gene, which translates as a polyglutamine repeat in the protein product. A fairly broad range of trinucleotide repeats (9-35) has been identified in normal controls, and repeat numbers in excess of 40 have been described as pathological. The huntingtin locus is large, spanning 180 kb and consisting of 67 exons. The huntingtin gene is widely expressed and is required for normal development. It is expressed as 2 alternatively polyadenylated forms displaying different relative abundance in various fetal and adult tissues. The larger transcript is approximately 13.7 kb and is expressed predominantly in adult and fetal brain whereas the smaller transcript of approximately 10.3 kb is more widely expressed. The genetic defect leading to Huntington's disease may not necessarily eliminate transcription, but may confer a new property on the mRNA or alter the function of the protein. One candidate is the huntingtin-associated protein-1, highly expressed in brain, which has increased affinity for huntingtin protein with expanded polyglutamine repeats. This gene contains an upstream open reading frame in the 5' UTR that inhibits expression of the huntingtin gene product through translational repression. [provided by RefSeq, Jul 2016]

HTT Gene-Disease associations (from GenCC):

• Huntington disease

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
• Lopes-Maciel-Rodan syndrome

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• juvenile Huntington disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002583623).
• BP6: Variant 4-3135947-G-A is Benign according to our data. Variant chr4-3135947-G-A is described in ClinVar as Benign. ClinVar VariationId is 1615277.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0589 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001388492.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HTT	NM_001388492.1	MANE Select	c.2677G>A	p.Gly893Arg	missense	Exon 20 of 67	NP_001375421.1
	HTT	NM_002111.8		c.2677G>A	p.Gly893Arg	missense	Exon 20 of 67	NP_002102.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HTT	ENST00000355072.11	TSL:1 MANE Select	c.2677G>A	p.Gly893Arg	missense	Exon 20 of 67	ENSP00000347184.5
	HTT	ENST00000510626.5	TSL:1	n.2776G>A		non_coding_transcript_exon	Exon 7 of 53
	HTT	ENST00000681528.1		c.2419G>A	p.Gly807Arg	missense	Exon 20 of 68	ENSP00000506116.1

Frequencies

GnomAD3 genomes AF: 0.0408 AC: 6210 AN: 152172 Hom.: 168 Cov.: 32

Gnomad AFR AF: 0.0111

Gnomad AMI AF: 0.0439

Gnomad AMR AF: 0.0519

Gnomad ASJ AF: 0.0323

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0209

Gnomad FIN AF: 0.0438

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0604

Gnomad OTH AF: 0.0530

GnomAD2 exomes AF: 0.0414 AC: 9882 AN: 238800 AF XY: 0.0421

Gnomad AFR exome AF: 0.0120

Gnomad AMR exome AF: 0.0365

Gnomad ASJ exome AF: 0.0301

Gnomad EAS exome AF: 0.0000583

Gnomad FIN exome AF: 0.0407

Gnomad NFE exome AF: 0.0603

Gnomad OTH exome AF: 0.0479

GnomAD4 exome AF: 0.0538 AC: 78062 AN: 1450868 Hom.: 2325 Cov.: 29 AF XY: 0.0528 AC XY: 38139 AN XY: 721730

African (AFR) AF: 0.00882 AC: 290 AN: 32866

American (AMR) AF: 0.0376 AC: 1578 AN: 42008

Ashkenazi Jewish (ASJ) AF: 0.0309 AC: 801 AN: 25920

East Asian (EAS) AF: 0.000102 AC: 4 AN: 39294

South Asian (SAS) AF: 0.0193 AC: 1618 AN: 83902

European-Finnish (FIN) AF: 0.0404 AC: 2151 AN: 53304

Middle Eastern (MID) AF: 0.0502 AC: 287 AN: 5722

European-Non Finnish (NFE) AF: 0.0617 AC: 68356 AN: 1107892

Other (OTH) AF: 0.0496 AC: 2977 AN: 59960

GnomAD4 genome AF: 0.0408 AC: 6211 AN: 152290 Hom.: 168 Cov.: 32 AF XY: 0.0393 AC XY: 2925 AN XY: 74466

African (AFR) AF: 0.0111 AC: 461 AN: 41570

American (AMR) AF: 0.0518 AC: 792 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0323 AC: 112 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5192

South Asian (SAS) AF: 0.0207 AC: 100 AN: 4824

European-Finnish (FIN) AF: 0.0438 AC: 465 AN: 10606

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0604 AC: 4111 AN: 68010

Other (OTH) AF: 0.0525 AC: 111 AN: 2116

Alfa AF: 0.0535 Hom.: 737

Bravo AF: 0.0403

TwinsUK AF: 0.0615 AC: 228

ALSPAC AF: 0.0612 AC: 236

ESP6500AA AF: 0.0133 AC: 49

ESP6500EA AF: 0.0600 AC: 492

ExAC AF: 0.0425 AC: 5135

Asia WGS AF: 0.0110 AC: 38 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.38
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.51	D
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	2.0	M
PhyloP100		5.7
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.30
Sift	Uncertain	0.0030	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.084
MutPred		0.43		Gain of solvent accessibility (P = 0.0171)
MPC		0.13
ClinPred		0.014	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.57
gMVP		0.64
Mutation Taster		=86/14	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs363075; hg19: chr4-3137674; COSMIC: COSV61861243;